Date on Master's Thesis/Doctoral Dissertation

12-2011

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Anatomical Sciences and Neurobiology

Committee Chair

Kumar, Ashok

Author's Keywords

Skeletal muscle; Muscle regeneration; Cell signaling; Stem cells; Muscle atrophy

Subject

Musculoskeletal system--Physiology; Muscular atrophy

Abstract

Skeletal muscle is the most abundant tissue in our body that provides a structural framework and regulates important biological processes. It is also a primary reservoir of protein. Skeletal muscle maintains its structural and functional integrity by finely balancing the rates of protein synthesis and degradation. Skeletal muscle also has a very well defined regeneration program to cope with muscle injuries. A disruption in any of these delicately balanced intracellular mechanisms of skeletal muscle results in devastating conditions such as atrophies and chronic injuries. Majority of these debilitating conditions in skeletal muscle eventually lead to morbidity and increased mortality and do not have available therapeutic interventions. The main aim of my research has been focused on understanding the role of an important adapter molecule tumor necrosis factor associated factor 6 (TRAF6) in skeletal muscle wasting and injury-induced regeneration. Using genetic mouse models of TRAF6 muscle-specific knock-out, this study has elucidated the regulatory role of TRAF6 in intracellular signaling pathways in skeletal muscle catabolism. In atrophic conditions, accelerated proteolytic degradation and activation of major catabolic mechanisms of skeletal muscle (p38MAPK, c-Jun N-terminal kinase, AMP activated kinase and NF-KB) cause of loss of skeletal muscle protein content and thus lead to reduced muscle fiber size and contractile ability. Myosin heavy chain, a major contractile protein of skeletal muscle is selectively targeted for degradation in response to different atrophic stimuli. In starvation-induced atrophy, endoplasmic reticulum stress and unfolded protein response were also found to be activated in addition to proteolytic mechanisms. Surprisingly, TRAF6 depletion in skeletal muscle of mice repressed activation of all these mediators of skeletal muscle atrophy and consequently, inhibited skeletal muscle atrophy. Taken together, this study has identified TRAF6 as an important regulator of skeletal muscle catabolic mechanisms in disuse and starvation-induced atrophy. Injury-induced regeneration of skeletal muscle is a highly complex interplay of different signaling networks and effectors. Our results show that TRAF6 activates pro-inflammatory signaling and promotes inflammation and necrosis in skeletal muscle and its depletion reduces inflammation and accelerates skeletal muscle regeneration.

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